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RESEARCH Open Access
Reduction of exacerbations by the PDE4 inhibitor
roflumilast - the importance of defining different
subsets of patients with COPD
Stephen I Rennard
1*
, Peter MA Calverley
2
, Udo M Goehring
3
, Dirk Bredenbröker
3
, Fernando J Martinez
4
Abstract
Background: As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all
patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has
been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected
populations was inconclusive. This led to the question of whether a responsive subset existed that could be
investigated further.
Methods: The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group
studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations
were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more
precisely defined patient subset.
Results: The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations
by 14.3 % compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic
bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006),
presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease,
p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more
patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs
8.3%).

Conclusions: This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of
COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations
aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with
roflumilast treatment.
Trials registration: ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729.
Background
Chronic obstructive pulmonary disease (COPD) is a
highly prevalent condition and a major cause of morbid-
ity and mortality worldwide [1-3]. As the disease pro-
gresses, patients with COPD report more frequent
exacerbations, which are associated with an increased
mortality risk and greater health care utilization, hospital
admissions and costs [4]. Worse, frequent exacerbations
are associated with a faster decline in lung function and
increased mortality [5].
Phosphodiesterase 4 (PDE4) inhibitors are effective
anti-inflammatory agents in animal models and have
been shown to reduce markers of inflammation in
COPD [6,7]. In a 6-month study in patients with moder-
ate-to-severe COPD (post-bronchodilator mean forced
expiratory volume in 1 second [FEV
1
] 54% predicted
[8]), the PDE4 inhibitor roflumilast improved lung func-
tion and reduced exacerbations [9]. This led to two sub-
sequent 12-month studies (M2-111, reported here for
the first time, and M2-112 [10]) in patients with severe-
* Correspondence:
1
Nebraska Medical Center, Omaha, USA

Full list of author information is available at the end of the article
Rennard et al. Respiratory Research 2011, 12:18
/>© 2011 Rennard et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Cre ative Commons
Attribution License (h ttp://creativecom mons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
to-very-severe COPD, which confirmed the positive
effect of roflumilast on lung function. Although neither
study demonstrated a significant effect on exacerbations,
which was a co-primary endpoint, a trend towards lower
overall exacerbation rates with roflumilast was seen in
each study.
As COPD is a highly heterogeneous disease [11], the
possibility that a subset of the COPD population might
be more responsive to roflumilast-induced reduction i n
exacerbations was entertaine d. To test this hypothesis,
the results from the two 12-month studies, that were
inconclusive with regard to exacerbations, were pooled
and a series of post-hoc analyses performed. The results
of these analyses are presented in the current report.
The heterogeneity of the COPD patient population is
well recognized. However, clinically meaningful subsets
of patients with COPD have been difficult to define and
several l arge observational studies are currently under-
way to attempt to address this problem [12-14]. The
current post-hoc analysis of pooled clinical trial data
was conducted in order to define a s ubset of patients
with COPD who are likely to respond to a specific ther-
apy - a ‘ hypothesis-generating’ exercise that has been
confirmed in subsequent clinical trials [15]. The
approach described in the current study may be applic-

able to define other meaningful subsets of patients with
COPD.
Methods
Patients and study design
M2-111 was conducted between December 2003 and
December 2005 in 188 centers in 6 countries, and M2-
112 between January 2003 and Octobe r 2004 in 159
centers in 14 countries. Full details of the methodology,
patient selection and efficacy assessments have been
published previously for M2-112 [10]. (For details of the
clinical design of both trials, and a CONSORT diagram
for the unpublished study M2-111, see Additional file 1,
Appendix 1, and Additional file 1, Figure S1).
The studies were ap proved by local ethical rev iew
committees (see Additional file 1, Appendix 2 for a list
of committee names and appro val numbers) and p er-
formed in accordance with the Declaration of Helsinki
and Good Clinical Practice Guidelines.
Statistical analysis
The statistical analysis was performed as described pre-
viously [10] with some modifications (i.e., all data were
re-analyzed based on the methods used in two other
52-week studies) [15]. The primary endpoint (pre-
bronchodilator FEV
1
) and main secondary lung function
endpoint (post-bronchodilator FEV
1
) were eval uated
using a repeated measures analysis of covariance

(ANCOVA, mixed effects model). This model is able to
handle missing data points by taking into account all
available data from scheduled visits of the treatment
period and the correlation in repeated measurements.
The c o-primary endpoint of rate of moderate or severe
exacerbations per patient per year was defined by the
need for oral or parenteral corticosteroid treatment,
hospitalization, or death, and was evaluated using a
Poisson regression model with a correction for over-
dispersion. The natural logarithm of the trial duration,
in terms of years, was included in this model as an off-
set variable to correct for the time a patient participated
in the trial. Rate ratios from this model were expressed
as percent reductions. Time to onset of exacerbations
was analyzed using a Cox proportional hazards regres-
sion model. For the regression models (ANCOVA, Pois-
son, and Cox), the covariates included treatment
(roflumilast/placebo), age, sex, smoking status (current/
former smoker), study, concomitant treatment with
inhaled corticosteroi ds (ICS) and country pool (only for
the overall populatio n). In the Poisson regression analy-
sis, baseline post-bronchodilator FEV
1
(% of predicted
value) was also included as a covariate. Adverse events
were analyzed using descriptive statistics.
Data are presented as mean and standard deviation
(SD), unless otherwise indicated. Safety endpoints were
analyzed using descriptive statistics. Results are pre-
sented as mean ± SD or standard error (SE) as appropri-

ate, with data derived from t he statistical modeling
being adjusted means. All p values are reported two-
sided with a level of significance of 0.05.
To identify subpopulations, the two primary endpoints
were analyzed additionally in subgroups stratified by
sex, smoking status, concomitant use of ICS, concom i-
tant use of anticholinergics, study completion status,
COPD severity (severe, very severe), history of chronic
bronchitis or emphysema (investigator-diagnosed), as
well as co ugh and spu tum score during the week before
randomization.
Results
Patients
Of 3630 patients enrolled into the run-in period, 2686
patients met the inclusion criteria and were randomized
to treatment; 1905 patients comp leted the studies
(Figure 1). The reasons for withdrawal were similar
between groups except for adverse events, which
occurred more frequently with roflumilast.
Demographics an d baseline characteristics of the ran-
domized patients were comparable between treatments
(Tabl e 1). Patie nts were predominantly male, and spiro-
metric severity was consistent with severe-to-very-severe
disease [8]. FEV
1
reversibility to short-acting b
2
-agonists
was similar in both treatment groups. As the inclusion
criterion of FEV

1
reversibility to short-acting b
2
-agonists
Rennard et al. Respiratory Research 2011, 12:18
/>Page 2 of 10
≤15% was defined only in study M2-112, mean reversi-
bility was lower in M2-112 (11%) than in M2-111
(19%). All other demographic and baseline characteris-
tics were comparable (or with only small differences not
considered clinically relevant) between the two studies.
On study entry and during the course of the studies,
about 60% of the patients continued to receive ICS,
while 60% continued to receive short-acting anticholi-
nergics (Table 1).
Exacerbations
The rate of moderate-to-severe exacerbations in the
pooled analysis was 14.3% lower with roflumilast com-
pared with placebo (0.52 vs 0.61 exac erbations per year;
p = 0.026, Table 2 and Figure 2). However, the median
time to first moderate or severe exacerbation was com-
parable in the rof lumilast and place bo groups (120 and
126 days, respectively, p = 0.236).
There w ere several subgroups in which the exacerba-
tion rate appeared lower with roflumilast compared with
placebo (Table 2), in cluding patients with chronic bron-
chitis with or without emphysema (26.2% reduction in
exacerbation rate vs placebo; p = 0.001). Other sub-
groups, such as current vs former smokers or those
based on spirometrically defined COPD severity, showed

no or little difference in the exacerbation rate with
roflumilast. Patients receiving concomitant ICS experi-
enced an 18.8% reduction in exacerbations compared
with placebo (p = 0.014). Patients not receiving ICS
exhibited no clinical benefit compared with plac ebo
(Table 2). A significant reduction in exacerbation rate in
favor of roflumilast was also seen in the subgroup of
patients receiving concomitant short-acting anticholiner-
gic treatment (18.3%, p = 0.012).
Lung function
Treatment with roflumilast resulted in significant
improvement in pre-bronchodilator FEV
1
compared
with placebo. In the combined analysis, the improve-
ment was evid ent at Week 4 (first measured time point)
and maintained throughout the 52 weeks of the studies.
After 52 weeks, the change in pre-bronchodilator FEV
1
from baseline with r oflumilast versus pl acebo was 51
mL (SE 7 m L, p < 0.0001), while the change in post-
bronchodilator FEV
1
with roflumilast vs placebo was
53 mL (SE 8 mL, p < 0.0001) (Figure 3; and see Addi-
tional file 1, Table S1). In contrast to the effect on
exacerbations, roflumilast consistently showed a signifi-
cant improvement compared with placebo in pre-
bronchodilator FEV
1

in all subgroups; the same was
Figure 1 Trial profiles of M2-111 and M2-112. Percentages are based on the number of randomized patients in a treatment group.
Rennard et al. Respiratory Research 2011, 12:18
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seen for post-bronchodilator FEV
1
(see Additional file 1,
Table S1). In the group of patients with COPD asso-
ciated with chronic bronchitis or combined emphysema
and chronic bronchitis, those patients receiving con-
comitant ICS showed a greater improvement from base-
line with roflumilast vs placebo (see Additional file 1,
Table S1).
Health status
In the combined analysis, treatment with roflumilast
resulted in no significant improvement in St George’s
Respiratory Questionnaire (SGRQ) total score compared
with placebo. In contrast, in the subgroup analysis (Fig-
ure 4; and see Additional file 1, Table S2), a significant
improvement in SGRQ total score was observed for
individuals with chronic bronchitis (p = 0.0265). This
difference was also evident in patients with chronic
bronchitis who were concurrently treated with ICS (p =
0.0397).
Safety
Adverse events were similar to those reported for roflu-
milast in p revious studies (see Additional file 1, Appen-
dix 3). Importantly, roflumilast (compared with placebo)
Table 1 Demographics and baseline characteristics
Pooled study

population
M2-111 M2-112
Characteristics Roflumilast Placebo Roflumilast Placebo Roflumilast Placebo
No. of patients 1327 1359 567 606 760 753
Age (years) 64.7 (9.2) 64.4 (8.9) 64 (8.7) 64 (8.8) 65 (9.6) 64 (9.1)
Male sex, n (%) 958 (72.2) 974 (71.7) 387 (68.3) 400 (66.0) 571 (75.1) 574 (76.2)
Body mass index, kg/m
2
25.7 (5.3) 25.7 (5.4) 26.0 (5.7) 25.8 (5.7) 25.4 (5.0) 25.6 (5.1)
Smoking status
Current smokers, n (%) 529 (40) 530 (39) 240 (42) 265 (44) 289 (38) 265 (35)
Former smokers, n (%) 798 (60) 829 (61) 327 (58) 341 (56) 471 (62) 488 (65)
Pack-years (± SD) 46 (25.6) 48 (26.6) 50 (28.2) 51 (26.7) 42 (22.9) 45 (26.2)
Pre-bronchodilator FEV
1
(L) 1.0 (0.4) 1.0 (0.3) 0.96 (0.4) 0.93 (0.3) 1.04 (0.4) 1.06 (0.3)
Post-bronchodilator FEV
1
(L) 1.13 (0.4) 1.13 (0.4) 1.12 (0.4) 1.09 (0.4) 1.13 (0.4) 1.15 (0.4)
Post-bronchodilator FEV
1
(% predicted) 37.1 (10.5) 36.8 (9.9) 36.8 (10.7) 36.1 (9.7) 37.3 (10.3) 37.3 (9.9)
Reversibility:
Change in FEV
1
(mL) 126.9
(140.1)
125.8
(149.1)
165.6

(142.8)
160.9
(150.0)
98.1 (130.9) 97.6
(142.4)
Change in FEV
1
(%) 14.6 (16.4) 14.4 (16.4) 19.4 (17.1) 19.1 (17.6) 11.0 (14.8) 10.6 (14.4)
FEV
1
/FVC (%) 41.8 (11.3) 41.8 (10.7) 43.3 (10.7) 43.1 (10.1) 40.6 (11.5) 40.7 (11.2)
COPD severity, n (%)
Very severe COPD 329 (24.8) 345 (25.4) 148 (26.1) 169 (27.9) 181 (23.8) 176 (23.4)
Severe COPD 864 (65.1) 909 (66.9) 356 (62.8) 399 (65.8) 508 (66.8) 510 (67.7)
COPD history, n (%)
Emphysema 352 (26.5) 413 (30.4) 193 (34.0) 234 (38.6) 159 (20.9) 179 (23.8)
Chronic bronchitis ± emphysema 817 (61.6) 847 (62.3) 374 (66.0) 372 (61.4) 443 (58.3) 475 (63.1)
Pre-study medication for COPD, n (%)* 1273 (96) 1291 (95) 537 (95) 557 (92) 736 (97) 734 (98)
Inhaled short-acting b agonists 729 (55) 734 (54) 315 (56) 333 (55) 414 (55) 401 (53)
Inhaled corticosteroids 579 (44) 588 (43) 218 (38) 225 (37) 361 (48) 363 (48)
Inhaled short-acting anticholinergics 549 (41) 570 (42) 189 (33) 192 (32) 360 (47) 378 (50)
Inhaled long-acting b
2
-agonists 353 (27) 379 (28) 143 (25) 140 (23) 210 (28) 239 (32)
Xanthines 320 (24) 316 (23) 113 (20) 118 (20) 207 (27) 198 (26)
Inhaled combination of b
2
-agonists and short-acting
anticholinergics
323 (24) 314 (23) 168 (30) 174 (29) 155 (20) 140 (19)

Inhaled combination of corticosteroids and long-acting
b
2
-agonists
260 (20) 263 (19) 131 (23) 139 (23) 129 (17) 124 (17)
Concomitant short-acting anticholinergics, n (%) 786 (59) 818 (60) 334 (59) 350 (58) 452 (60) 468 (62)
Concomitant inhaled corticosteroids, n (%) 809 (61) 813 (60) 328 (58) 332 (55) 481 (63) 481 (64)
Data are expressed as mean (SD), unless otherwise stated.
* Patients could have received more than one of these medications.
Rennard et al. Respiratory Research 2011, 12:18
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was not associated with an increase in adverse events in
the subgroups that experienced a g reater reduction in
exacerbations with roflumilast compared with placebo
(Table 3; and see Additional file 1, Appendix 3). Conco-
mitant ICS did not affect the adverse eve nt profile of
roflumilast.
Discussion
PDE4 inhibitors have demonstrated an anti-inflamma-
tory effect in animal models and patients with COPD
[6,7]. In two previous 12-month studies, in patients with
severe-to-very-severe COPD, roflumilast improved lung
function, although neither study demonstrated a signifi-
cant effect on exacerbations [10]. Given the pleiotropic
effects of PDE4 inhibition [16], we hypothesized that a
roflumilast effect could be present in specific subgroups
of patients with COPD. In addition, exacerba tion rates
in the individual trials were lower than expected. Com-
bining the datasets of the two studies improved statisti-
cal power and allowed definition of the patients more

likely to respond to roflumilast. In the combined dataset,
a significant effect of roflumilast was observed for the
entire population but, importantly, the subgroup analysis
showed a preferential effect in patients with chronic
Table 2 Analysis of exacerbations (moderate to severe)
Roflumilast Placebo Effect size
Characteristic n Rate n Rate Rate ratio (SE) Change (%) p value
M2-111 567 0.595 606 0.692 0.860 (0.085) -14.0 0.129
M2-112 760 0.455 753 0.537 0.848 (0.081) -15.2 0.085
Pooled results
Overall 1327 0.523 1359 0.610 0.857 (0.059) -14.3 0.026
Sex
Female 369 0.612 385 0.648 0.943 (0.117) -5.7 0.637
Male 958 0.495 974 0.609 0.813 (0.071) -18.7 0.018
Smoking status
Current smoker 529 0.529 530 0.643 0.823 (0.094) -17.7 0.086
Former smoker 798 0.568 829 0.663 0.857 (0.078) -14.3 0.092
Concomitant treatment
ICS 809 0.720 813 0.886 0.812 (0.068) -18.8 0.014
No ICS 518 0.424 546 0.460 0.923 (0.124) -7.7 0.550
Concomitant treatment
Short-acting anticholinergics 786 0.706 818 0.864 0.817 (0.066) -18.3 0.012
No short-acting anticholinergics 541 0.368 541 0.370 0.995 (0.147) -0.5 0.974
COPD severity
Very severe COPD 329 0.738 345 0.885 0.833 (0.101) -16.7 0.132
Severe COPD 864 0.526 909 0.609 0.864 (0.080) -13.6 0.113
COPD history
Emphysema 352 0.579 413 0.586 0.989 (0.120) -1.1 0.925
Chronic bronchitis ± emphysema 817 0.486 847 0.659 0.738 (0.068) -26.2 0.001
Chronic bronchitis ± emphysema with concomitant ICS 492 0.608 493 0.871 0.698 (0.077) -30.2 0.001

Chronic bronchitis ± emphysema: no ICS 325 0.391 354 0.462 0.845 (0.140) -15.5 0.310
Cough score at Week 0
≥ 1 (average/day) 896 0.560 939 0.708 0.791 (0.067) -20.9 0.006
< 1 (average/day) 395 0.523 385 0.508 1.030 (0.142) 3.0 0.830
Sputum score at Week 0
≥ 1 (average/day) 829 0.576 862 0.700 0.822 (0.074) -17.8 0.030
< 1 (average/day) 458 0.512 460 0.549 0.933 (0.113) -6.7 0.565
Study completion status
Completers 894 0.453 1011 0.573 0.790 (0.064) -21 0.004
Non-completers 433 1.126 348 1.155 0.975 (0.113) -2.5 0.826
Rates (per patient/year), Rate ratio and two-sided p-values (significance level 5%) are based on a Poisson regression model with the following factors and
covariates: treatment, age, sex, smoking status, baseline post-bronchodilator FEV
1
(% predicted), study, concomitant treatment with ICS and country pool (only
for the overall population).
Rennard et al. Respiratory Research 2011, 12:18
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bronchitis or with high cough or sputum scores in the
week prior to randomization, and in patients taking con-
comitant ICS or anticholinergics. These results sug-
gested that it is possible to identify a subset of patients
that is more likely to benefit from roflumilast with
regard to reduced exacerbations.
In subjects with chronic bronchitis, this post-hoc,
pooled analysis suggested a benefit of roflumilast on
health status as measured by the SGRQ. The difference,
compared with placebo, of -1.073 units did not achieve
the c onventional minimum important dif ference of
4 units, but was statistically significant and similar to
differences seen between therapy i n other 1 -year trials

[17]. This is consistent with the benefit in SGRQ result-
ing from the reduction in exacerbations.
Interestingly, roflumilast demonstrated a consistent
effect on airflow, assessed as both pre- and post-bronch-
odilator FEV
1
across all subgroups. There are several
possibilities why the effect on exacerbations may be
limited to a subset of patients. First, the subsets may
identify those individuals at greater ri sk for exacerba-
tions. A therapeutic benefit can be observed only if the
individuals are at risk. Alternatively, as roflumilast can
affect many aspects of the inflammatory response, it is
possible that an anti-inflammatory effect, such as reduc-
tion in airway edema, may account for the improved
airflow and a different mechanism accounts for the
reduced exacerbations.
The effects seen with roflumilast in symptomatic
patients and in patients with chronic bronchitis are
comparable with those obtained by ICS/long-acting
bronchodilator combination therapy [18-20]. The
enhanced benefit of roflumilast in patients with chronic
bronchitis is particularly interesting as this phenotype
has been shown to be associated with serum markers
indicative of increased systemic inflammation [21].
These patients a re also at higher risk for mortality at a
younger age [21]. The tren d for a greater benefit in
Overall
Female
Male

Current smokers
Former smokers
ICS: yes
ICS: no
Anticholinergic: yes
Anticholinergic: no
Completers
Non-completers
Very severe COPD
Severe COPD
Emphysema
Chronic bronchitis ± emphysema
Chronic bronchitis ± emphysema + ICS
Chronic bronchitis ± emphysema – ICS
Cough score ≥1
Cough score <1
Sputum score ≥1
Sputum score <1
1.210.80.60.40.20
Favors placeboFavors roflumilast
1.4
Figure 2 Rate ratios and 95% CIs for reduction in COPD exacerbations with roflumilast by patient subgroup. Error bars represent 95% CIs.
Rennard et al. Respiratory Research 2011, 12:18
/>Page 6 of 10
patients receiving concomitant ICS may be a marker of
disease severity. This patient subgroup is at higher risk
for exacerbations, indicated by the higher exacerbation
rate in the placebo group in ICS-treated patients vs non
ICS-treated patients (0.886 vs 0.460). That these indivi-
duals had been i dentified by their clinicians for treat-

ment with ICS suggests that they were recognized as
being at risk clinically and that further reductions in
exacerbations and improved airflow were observed with
roflumilast in this group suggests that a PDE4 inhibitor
may add incremental value to ICS therapy.
Although the incidence of adverse events was compar-
able between treatment groups, there were more discon-
tinuations due to adverse events with roflumilast
compared with placebo. The majority of adverse events
in both groups lasted less than 4 weeks and resolved
with continued treatment. The incidence of treatment-
related adverse events was low and similar to those
reported previously [9,18]. These treatment-related
events included diarrhea, nausea, and headache, which
are all adverse events known to be associated with
PDE4 inhibitors [22]. Weight loss was more frequent
with roflumilast treatment. Several serious adverse
events and deaths occurred, as would be expected in
this patient population. The number of deaths was
higher in the placebo group and most fatal events were
related to COPD. A slightly higher incidence of adverse
events and s erious adverse events was seen in patients
receiving ICS; this was seen in both the roflumilast and
placebo groups. Oropharyngeal adverse events typically
associated with ICS treatment, such a s oral candidiasis,
dysphonia, and pharyngitis, as well as pneumonia, were
more frequently reported in patients treated with ICS,
but there was no indication that roflumilast increased
Pooled results: all patients
Female

Male
Completer
Non-completer
Very severe COPD
Severe COPD
Emphysema
Chronic bronchitis ± emphysema
Current smoker
Former smoker
Anticholinergic: yes
Anticholinergic: no
ICS: yes
ICS: no
Chronic bronchitis ± emphysema + ICS
Chronic bronchitis ± emphysema – ICS
M2-111: all patients
M2-112: all patients
Cough score ≥1
Cough score <1
Sputum score ≥1
Sputum score <1
0.080.060.040.020–0.02–0.04
Pre-bronchodilator FEV
1
(L)
0.1
Figure 3 Differences and 95% CIs between roflumil ast and placebo for increase in pre-bronc hodilator FEV
1
(L) by patient subgroup .
Error bars represent 95% CIs.

Rennard et al. Respiratory Research 2011, 12:18
/>Page 7 of 10
ICS-associated adverse events. Importantly, subjects with
chronic bronchitis who were more likely to benefit from
roflumilast did not experience an increased incidence of
adverse events. On the contrary, there was a trend for
these individuals to have fewer of the adverse events
(nausea, diarrhea, and weight loss) that are associated
with PDE4 inhibitors.
There are limitations to the pooled analysis presented
in this manuscript, which includes both fully published
and previously unpublished results. The post-hoc nature
of the comparisons, particularly those in various subsets,
must be interpreted with caution and serve principally
as hypothesis generating. However, these results were
used to design two additional randomized trials that
specifically evaluated patients wi th severe COPD asso-
ciated with chronic bronchitis, a group expected to be
more likely to experience reductions in exacerbations
with roflumilast. In this defined population, a significant
beneficial eff ect of roflumilast compared with placebo in
both lung function and exacerbation rate was observed
in both studies [15]. In this context, the sequence of stu-
dies is crucial. Following a phase 2 trial that showed
promising results [9], two ‘ convention al’ 12-month
phase 2 trials (Study M2-111, reported here for the first
time, and M2-112 [10]) were conducted, both of w hich
showed improvements in FEV
1
but demonstrated only a

trend toward exacerbati on reduction. The pooled analy-
sis presented here demonstrated that a subset of the
COPD population appea red to account for all the bene-
fit with regard to exacerbations. This ‘ hypo thesis’
formed the basis of two subsequent trials [15] which
demonstrated the efficacy of roflumilast for exacerbation
reduction in this subset.
Novel therapies for COPD a re urgently needed [11].
The current manuscript describes the successful use of
a strategy for identification of a responding subset from
Figure 4 Differences and 95% CIs between roflumilast and placebo for changes in St George’s Respiratory Questionnaire (SGRQ) total
score by patient subgroup. Error bars represent 95% CIs.
Rennard et al. Respiratory Research 2011, 12:18
/>Page 8 of 10
clinical trial data that was then confirmed in two pro-
spective, randomized, placebo-controlled clinical trials.
At present, segmentation of meaningful sub-populations
of COPD patients is difficult, although seve ral large
observational studies are addressing this question. The
current study demonstrates that this goal can also be
achieved by post-hoc analysis of responses to a clinical
intervention.
Conclusions
This post-hoc, pooled analysis of two large-scale trials in
patients with severe and very severe COPD showed a
significant reduction in exacerbations with roflumilast
treatment and identi fied a subgroup of patients who are
most likely to benefit from treatment with roflumilast,
namely those patients with chronic bronchitis. In addi-
tion there was a greater effect in those patients taking

concomitant ICS. Identification of a subgroup of
patients more likely to respond to therapy is consistent
with the concept that the COPD population includes
multiple phe notypes and is a step towards personalized
medicine, matching therapy to phenotype [11,23,24].
Importantly, identification of a responding subset can
facilitate drug development by increasing the ability of
clinical trials to show a benefit. In this regard, the analy-
sis presented in the current report was used to design
subsequent clinical trials that have demonstrated
the clinical efficacy of roflumilast in reducing COPD
exacerbations. This is the first time such an approach
has been used successfully to aid a drug development
program in COPD.
Additional material
Additional file 1: Appendices 1-3, Table S1, Table S2, and Figure S1.
Appendix 1: Trial design; Appendix 2: IRB approval; Appendix 3: Adverse
events; Table S1: Lung function results summary table (change in lung
function variable after 52 Weeks compared wit h baseline); Table S2: St
George’s Respiratory Questionnaire (SGRQ) total score: change after 52
Weeks compared with baseline; Figure S1: Trial profile of M2-111.
Additional file 2: List of investigators for Studies M2-111 and M2-
112. M2-111 investigators; M2-112 investigators.
Abbreviations
ANCOVA: Analysis of covariance; COPD: chronic obstructive pulmonary
disease; FEV
1
: forced expiratory volume in 1 second; ICS: inhaled
corticosteroids; PDE4: phosphodies terase 4; SD: standard deviation; SE:
standard error; SGRQ: St George’s Respiratory Questionnaire.

Acknowledgements
The authors would like to thank all of the investigators who recruited and
treated patients at the centers involved in these studies (see Additional file 2
for M2-111 and M2-112 investigators), and Manja Brose (Nycomed GmbH,
Konstanz, Germany) for statistical analysis.
The studies in this report were supported by Nycomed GmbH, Konstanz,
Germany, who provided funding for the design, collection, analysis and
interpretation of data, and the writing and submission of the manuscript.
Christine Groves and Caroline Howell, medical writers, and Paul Wilmott, a
medical editor, for and on behalf of Caudex Medical, Oxford, UK, provided
editorial assistance with the manuscript, supported by Nycomed GmbH,
Konstanz, Germany.
Table 3 Adverse events
Subgroup All patients COPD history CB ± emphysema and ICS treatment
Emphysema CB ± emphysema With ICS Without ICS
Treatment (n) Rof
(1327)
Pbo
(1359)
Rof
(352)
Pbo
(413)
Rof
(817)
Pbo
(847)
Rof
(492)
Pbo

(493)
Rof
(325)
Pbo
(354)
Adverse events, n (% of patients)
All adverse events 1081
(81.5)
1089
(80.1)
309
(87.8)
344
(83.3)
642
(78.6)
673
(79.5)
402
(81.7)
399
(80.9)
240
(73.8)
274
(77.4)
All serious adverse events 263
(19.8)
264
(19.4)

73
(20.7)
81
(19.6)
154
(18.8)
152
(17.9)
112
(22.8)
109
(22.1)
42
(12.9)
43
(12.1)
Adverse events related to study
medication
285
(21.5)
113
(8.3)
91
(25.9)
39
(9.4)
134
(16.4)
67
(7.9)

77
(15.7)
35
(7.1)
57
(17.5)
32
(9.0)
Adverse events leading to study
discontinuation
235
(17.7)
136
(10.0)
52
(14.8)
40
(9.7)
94
(11.5)
56
(6.6)
65
(13.2)
40
(8.1)
29
(8.9)
16
(4.5)

Most
common adverse events (≥ 5% of patients in any treatment group), %
COPD exacerbation 42.9 48.0 45.5 47.7 43.0 48.5 49.8 54.4 32.6 40.4
Diarrhea 12.1 2.9 18.5 3.4 7.1 3.1 8.3 3.2 5.2 2.8
Nausea 6.0 1.5 8.0 1.9 4.4 1.3 4.7 1.0 4.0 1.7
Weight loss 7.5 2.8 11.9 4.1 6.1 2.5 5.3 1.6 7.4 3.7
Nasopharyngitis 6.8 7.4 7.7 8.2 7.5 7.7 6.5 7.3 8.9 8.2
Pneumonia 2.8 4.0 1.7 2.9 3.5 4.1 4.3 5.7 2.5 2.0
Upper respiratory tract infection 5.4 6.3 7.4 9.2 5.4 5.5 4.5 5.1 6.8 6.2
Headache 6.9 3.0 8.5 5.3 5.6 2.1 6.1 2.2 4.9 2.0
Influenza 4.4 4.0 5.4 5.3 4.4 3.7 4.5 2.2 4.3 5.6
Rof = roflumilast; Pbo = placebo.
Rennard et al. Respiratory Research 2011, 12:18
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Author details
1
Nebraska Medical Center, Omaha, USA.
2
University Hospital Aintree,
Liverpool, UK.
3
Nycomed GmbH, Konstanz, Germany.
4
University of Michigan
Medical Center, Ann Arbor, USA.
Authors’ contributions
SIR contributed to the conception and design of these studies, the acquisition of
study d ata, and th e analysis and interpretation of these data. H e was fully
involved in the drafting and revision of this manuscript, and provided final
approval of its c onte nt ahead o f submission. PMAC contributed to the

conception and de sign of t hese studies, the a cqui sitio n of study data, and the
analysis and interpretation of these data. He was fully involved in the drafting
and revision o f this manuscript, and provided final approval of its content ahead
of submission. U-MG contributed to the c onception and design of these studies,
the acquisition of study d ata , and the analysis and i nterpre tatio n of these data.
He was f ully involved in the drafting and revision of this manuscript, and
provided final approval of its content ahead of submission. He had full access to
all of t he data in the study and he t akes full responsibility for the integr ity of all of
the data and the accuracy of the data analysis, includ ing and especially any
adverse effects. DB contributed to the conception and design of these studies,
the acquisition of study d ata , and the analysis and i nterpre tatio n of these data.
He was f ully involved in the drafting and revision of this manuscript, and
provided final approval of its content ahead of submission. FJM contributed to
the conception and des ign of the se studies, as well as the analysis and
interpretation of these data. He was fully involved in the drafting and revision of
this manuscript, and provided final a pprov al of its content ahead o f submission.
Competing interests
SIR has served on advisory boards and as a consultant for Almirall
Prodesfarma, Aradigm Corporation; AstraZeneca, Boehringer Ingelheim,
Defined Health, Eaton Associates, GlaxoSmithKline, MEDACorp, Mpex
Pharmaceuticals, Novartis, Nycomed, Otsuka Pharmaceutical, Pfizer, Pulmatrix,
Theravance, United BioSource Corporation, Uptake Medical, and
VantagePoint. He has served as a speaker or a member of a speaker’ s
bureau for: AstraZeneca, Novartis, Network for Continuing Education, Pfizer,
and SOMA. He has also received research funding from AstraZeneca,
BioMarck, Centocor, Novartis, and Nycomed.
PMAC has served on advisory boards for AstraZeneca, GlaxoSmithKline,
Nycomed, and Novartis. He has received research funding from
GlaxoSmithKline, Nycomed, and Boehringer Ingelheim, and has spoken at
meetings supported by AstraZene ca, GlaxoSmithKline, and Nycomed.

FJM has been a member of advisory boards for GlaxoSmithKline, Schering
Plough, Novartis, Nycomed, Genzyme, Forest/Almirall, MedImmune,
AstraZeneca, Potomac, Bayer, Elan, Talecris, and Roche. He has been on the
speaker’s bureau for Boehringer Ingelheim, GlaxoSmithKline, France
Foundation, MedEd, NACE, and AstraZeneca. He has also been a member of
steering committees for studies supported by Altana/Nycomed,
GlaxoSmithKline, Gilead, Actelion, Johnson/Johnson, Mpex, UCB, and the
National Institutes of Health. He has been an investigator in trials supported
by Boehringer Ingelheim and Actelion.
UMG and DB are employees of Nycomed GmbH, Konstanz, Germany.
Received: 23 November 2010 Accepted: 27 January 2011
Published: 27 January 2011
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doi:10.1186/1465-9921-12-18
Cite this article as: Rennard et al.: Reduction of exacerbations by the
PDE4 inhibitor roflumilast - the importance of defining different subsets
of patients with COPD. Respiratory Research 2011 12:18.
Rennard et al. Respiratory Research 2011, 12:18
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